Tuesday, November 15, 2005

Fibril Structure and Alzheimer Disease

3-D Structure of Alzheimer's Disease Filament Shows How It Zips Up Peptides

Newswise — Researchers have solved the three dimensional structure of the long thread-like fibers that fill the brains of Alzheimer's disease patients. The structure reveals the proteins that make up the fibrils lock onto each other much like a zipper on a jacket. This advance, reported in the Nov. 14th early online edition of Proceedings of the National Academy of Sciences (PNAS), helps illuminate the molecular roots of Alzheimer's and possibly other degenerative diseases of the brain.

“Now that we understand at an atomic level how these fibrils form, it might help researchers develop a biomarker test to diagnose Alzheimer's disease at an early stage, as well as drugs to treat it,” says the study's lead investigator, Salk Institute for Biological Studies scientist Roland Riek, Ph.D., who collaborated with researchers at the University of Lausanne and Roche pharmaceuticals, both in Switzerland

As a result of the study, Riek and his colleagues may now understand how a potential Alzheimer's disease medication now in clinical trials in Europe reacts to the fibril. The drug binds to the end of the fibril chain of beta amyloid proteins, halting their lethal accumulation, an early step in the formation of the amyloid plaque deposits that are a hallmark of Alzheimer's.

[snip]

The research team of the Salk Institute in collaboration with the University of Lausanne and Roche, developed new research techniques to determine the 3D structure that mimics the most common type of fibrils found in patients with the disease.

They discovered that beta amyloid proteins (peptides) that make up these fibrils attach to each other on one end with an ever-growing property.

“From this structure we can nicely see what happens physically, where the fibril forms a template on which to bind other amyloid peptides in an inter-collated way,” Riek says. “The way these peptides lock on to each other is like a zipper on a jacket.” Due to the ever-growing property the zipper binds more and more loose peptides together to produce dense “plaque” filaments that may be toxic to the functioning of brain nerve cells.